(NVKP-16-1-2016-0017 National Heart Program) Támogató: NKFIH
(GINOP-2.3.2-15-2016-00015) Támogató: GINOP
(TUDFO/47138-1/2019-ITM) Támogató: ITM
(3.6.2-16-2017-0006) Támogató: EFOP
Szakterületek:
Orvos- és egészségtudomány
BACKGROUND: Maintenance of cell viability during cold storage is a key issue in organ
transplantation. Methane (CH4) bioactivity has recently been recognized in ischemia/reperfusion
conditions; we therefore hypothesized that cold storage in CH4-enriched preservation
solution can provide an increased defense against organ dysfunction during experimental
heart transplantation (HTX).
METHODS: The hearts of donor Lewis rats were stored for 60 minutes in cold histidine-tryptophan-ketoglutarate
(Custodiol [CS]) or CH4-saturated CS solution (CS-CH4) (n = 12 each). Standard heterotopic
HTX was performed, and 60 minutes later, the left ventricular (LV) pressure-volume
relationships LV systolic pressure (LVSP), systolic pressure increment (dP/dtmax),
diastolic pressure decrement, and coronary blood flow (CBF) were measured. Tissue
samples were taken to detect proinflammatory parameters, structural damage (by light
microscopy), endoplasmic reticulum (ER) stress, and apoptosis markers (CCAAT/enhancer
binding protein [C/EBP] homologous protein, GRP78, glycogen synthase kinase-3 beta,
very low-density lipoprotein receptor, caspase 3 and 9, B-cell lymphoma 2, and bcl-2-like
protein 4), whereas mitochondrial functional changes were analyzed by high-resolution
respirometry.
RESULTS: LVSP and dP/dtmax increased significantly at the largest pre-load volumes
in CS-CH4 grafts as compared with the CS group (114.5 +/- 16.6 mm Hg vs 82.8 +/- 4.6
mm Hg and 3,133 +/- 430 mm Hg/s vs 1,739 +/- 169 mm Hg/s, respectively); the diastolic
function and CBF (2.4 +/- 0.4 ml/min/g vs 1.3 +/- 0.3 ml/min/g) also improved. Mitochondrial
oxidative phosphorylation capacity was more preserved (58.5 +/- 9.4 pmol/s/ml vs 27.7
+/- 6.6 pmol/s/ml), and cytochrome c release was reduced in CS-CH4 storage. Signs
of HTX-caused myocardial damage, level of ER stress, and the transcription of proapoptotic
proteins were significantly lower in CS-CH4 grafts.
CONCLUSION: The addition of CH4 during 1 hour of cold storage improved early in vitro
graft function and reduced mitochondrial dysfunction and activation of inflammation.
Evidence shows that CH4 reduced ER stress-linked proapoptotic signaling. (C) 2020
International Society for Heart and Lung Transplantation. All rights reserved.
